Can St John’s wort cause elevation of liver enzymes (ALT, AST)?

Can St. John's Wort Elevate Liver Enzymes?

Yes, St. John's wort can cause elevation of liver enzymes (ALT, AST) and has been associated with drug-induced liver injury, particularly when combined with other medications or in susceptible individuals.

Evidence of Hepatotoxicity

St. John's wort has documented hepatotoxic potential through multiple mechanisms:

Direct Hepatotoxicity

A case report demonstrated severe acute hepatitis with aminotransferase values exceeding 20× the upper limit of normal when St. John's wort was combined with peginterferon α 1. The patient developed:

• ALT >20× ULN
• INR prolongation
• Positive antinuclear antibodies (1:320)
• Required 6 months of corticosteroid therapy for resolution

Another case documented drug-induced liver injury from an herbal immunostimulant containing St. John's wort, with 2:

• ALT elevated to 2800 U/L (normal <32 U/L)
• AST elevated to 1776 U/L (normal <31 U/L)
• Total bilirubin 577 U/L (normal <21 U/L)
• Complete resolution after drug withdrawal

Mechanism: Enhanced Drug Metabolism

St. John's wort activates the PXR-CYP signaling pathway, leading to upregulation of CYP2E1 and CYP3A enzymes 3. This mechanism:

• Increases metabolic activation of hepatotoxic drugs (demonstrated with acetaminophen)
• Promotes glutathione depletion
• Exacerbates drug-induced liver injury when combined with other hepatotoxic agents

Clinical Implications

When to Suspect St. John's Wort-Related Liver Injury

Evaluate for St. John's wort use when encountering:

• Unexplained ALT/AST elevations ≥3× ULN with hepatitis symptoms
• ALT/AST ≥5× ULN without symptoms 4
• New liver enzyme abnormalities in patients taking other medications
• Acute hepatitis presentation with negative viral hepatitis markers 5

Risk Factors for Severe Injury

• Concurrent use with other hepatotoxic medications (interferons, acetaminophen, other drugs)
• Pre-existing liver disease
• Prolonged use (weeks to months)

Management Algorithm

Immediate actions when St. John's wort-related hepatotoxicity is suspected:

1. Discontinue St. John's wort immediately - this is the only effective treatment for idiosyncratic drug-induced liver injury 6

2. Assess severity using these thresholds:

   • ALT ≥3× ULN with total bilirubin ≥2× ULN = severe injury requiring hospitalization 6
   • ALT ≥8× ULN = interrupt all potentially hepatotoxic agents 6
   • Presence of symptoms (fatigue, nausea, vomiting, right upper quadrant pain) with ALT ≥3× ULN = close monitoring required 6

3. Exclude competing etiologies:

   • Viral hepatitis (A, B, C, EBV, CMV)
   • Biliary tract disease
   • Alcohol
   • Other hepatotoxic drugs 4
   • Autoimmune hepatitis (check ANA, especially if enzyme elevations persist) 5

4. Monitor closely:

   • Repeat ALT, AST, alkaline phosphatase, total bilirubin in 2-5 days 6
   • Check INR if bilirubin elevated or synthetic dysfunction suspected
   • Weekly monitoring until normalization

5. Consider corticosteroids if autoimmune features develop (positive ANA, persistent elevation after drug withdrawal) 1

Important Caveats

• Delayed discontinuation can result in irreversible liver failure and death 6
• St. John's wort is often not disclosed by patients as they consider it "natural" - specifically ask about herbal supplements 5
• Drug-drug interactions may not manifest immediately; hepatotoxicity can develop after weeks to months of use 5
• The hepatotoxic potential varies with preparation and dose, making risk assessment challenging

Bottom line: St. John's wort should be considered a potential cause of elevated liver enzymes, particularly in the context of unexplained hepatitis or when combined with other medications. Immediate discontinuation is essential when hepatotoxicity is suspected.